DESCRIPTION: Autism is a neurodevelopmental disorder characterized by impairments in reciprocal social interaction and communication and the presence of restricted and repetitive patterns of interest or behavior. With the improved surveillance and a broadening of the diagnostic criteria, the most recent prevalence study suggests that autism affects as many as 1 in 300 children in the US. Treatments are few and most have little impact on the very significant morbidity. Little is known about the etiology of autism, but it does have a strong genetic component. Despite this significant genetic effect studies over the past decade have clearly shown that the underlying genetics is complex with the likelihood that several genes acting independently as well as interactively significantly raise the risk of autism. With this realization the field of autism genetics is at a critical juncture. To move forward we must embrace new and creative paradigms to successfully dissect the genetic etiology of this disease. During the current funding period we have emphasized both innovative and established genomic approaches to begin teasing apart the complex weave of autism genetics. In our renewal we will expand and build on previous results embracing the paradigm that the wedding of new genomic technology with novel statistical methodology will bring about success. Specifically we propose to 1) Broaden our ascertainment scheme to include the full range of the autism spectrum disorder phenotype, 2) Identify the chromosome 19 autism gene, 3) Investigate a newly defined linkage to chromosome 12 in large extended multigenerational autism families, 4) Extend our studies of the GABA receptor subunits genes, 5) Identify clinically homogeneous subsets of patients and families and use the refined dataset to fine map ASD chromosomal regions and in candidate gene analyses, 6) Test for evidence of new gene/gene interactions to fully explain the spectrum of autism risk. These efforts will be integrated to address an important problem in childhood disease, the genetics of autism spectrum disorders.